What is Cystic Fibrosis?

Cystic Fibrosis (CF) is one of the most common, life threatening, inherited diseases, primarily affecting populations of white Caucasian descent, such as those of Europe, North America and Australasia (Table 1). CF affects about 1 in 2,500 newborn babies in the UK, and the estimated population of patients in the UK is currently around 9,000. CF is an autosomal monogenic recessive disorder for which there is no cure at present.

The mutated gene responsible for this disease was identified in 1989 as the cystic fibrosis transmembrane conductance regulator (CFTR) gene, found on chromosome 72. Over 1000 disease-associated mutations of this 1480 amino acid protein have been described3 (see Table 2 for some common mutations). Some mutations result in severe disease impacting many organ systems, while other mutations produce milder symptoms. The most common CFTR mutation, accounting for approximately 70% of all mutant CFTR alleles, is the delta F508 allele, a single phenylalanine amino acid deletion at position 508 in the protein3.

The CFTR gene product regulates and facilitates the transport of electrolytes across the epithelial cell membrane and other cellular membranes. CF patients have abnormalities with chloride conductance in and out of cells. The mis-folded CFTR protein is either non-functional at the cell surface, or is retained in the endoplasmic reticulum of the cell and is targeted for degradation1.

In spite of the fact that over 1000 CF-linked CFTR mutations described, less than 20 mutations occur at a frequency greater 0.1%, and only 5 mutations at a frequency more than 1%1.

Symptoms

CF is a pleiotropic disease affecting all exocrine epithelia, not just that of the lungs, therefore CF is a complex and demanding disease1. Most people with CF will suffer from chronic lung infections, gradually declining respiratory function and respiratory failure, which is the most common cause of premature death.

Early symptoms of CF are increased susceptibility to lung infections, persistent coughing, and heightened sputum production. As infecting microbes fail to be cleared, uncontrolled inflammation begins to cause permanent damage to the lung architecture, resulting in bronchiectasis and pulmonary hypertension and hypoxia4. End-stage CF requires the use of air masks or ventilators to mechanically assist breathing. CF can also lead to nutrient loss by the progressive scarring of the pancreas, which becomes dehydrated in a fashion similar to that of the lungs4.

Physiological aspects

Chloride ion flow through CFTR is required for normal function of epithelia that line airways and the intestinal tract and ducts in the pancreas, testes and sweat glands3. Without anion flow, water movement slows, and dehydrated mucus clogs ducts and collects in the lung where it ultimately leads to lethal bacterial infections3. In the healthy lung foreign particles are removed from the airways through the surface liquid layer over the beating cilia5. The depth of the liquid layer is regulated by a balance between the opposing processes of sodium absorption and chloride secretion5.

This mechanical clearance of mucus, known as the mucociliary escalator, is considered the primary innate airway defense mechanism4. Additionally normal functioning epithelia have a “chemical shield” with the production of salt-sensitive defensins that are secreted into the airway lumen, and the production of a low-salt (<50 mM NaCl) liquid on airway surfaces that activates the defensins, together protecting the lung against inhaled bacteria5,6. In CF patients chloride secretion is impaired while sodium absorption is increased, which causes mucus to accumulate. Respiratory pathogens which are usually removed by mucociliary escalator are no longer eradicated as the normally beating cilia are matted4. Respiratory pathogens therefore accumulate to develop into polymicrobial biofilm-mediated infections in the lower airways, and over time this causes lung inflammation.

For further information about CF, you are referred to the following websites:

http://www.cftr.info
http://en.wikipedia.org/wiki/Cystic_fibrosis
http://www.cysticfibrosis.org.uk
http://www.cff.org